This is a revised R15 application with the goal of evaluating the role of impulsivity as a potential mediator of the association between genetic variation in the serotonin neurotransmitter system and the propensity for engaging in health-risk behaviors (HRB). To this end, a cross-sectional design, structural equation modeling and simulated indices of serotonergic function will be used to examine the extent to which serotonin system genotypes, exposure to early-life stress and gender are associated with HRB, such as gambling, disordered eating, substance use, risky sex, and risky driving, and how impulsivity may mediate these relations. Questionnaire and laboratory measures of behavior and buccal cells for genotyping will be gathered from 500 undergraduate students. Measures of multiple varieties of impulsivity and of HRB will be used to characterize the behaviors in detail and to capture combined variance across these constructs. The overall hypothesis is that the influence of serotonin on the propensity to engage in HRB is mediated by impulsivity and that these relations may vary by gender. To test this hypothesis we propose the following Specific Aims: 1. to evaluate the relations among genetic variants in the serotonin system, impulsivity and HRB, and test whether these relations are moderated by gender. We will use a structural equation modeling approach to test these relations across levels of analysis from gene to complex behavior that may differ by gender. 2. To evaluate the utility of simulated serotonin function indices for predicting HRB. We will use a control system model to estimate unobserved serotonin function indices and will test whether they are better predictors of HRB than are directly observed measures (e.g. genotype, gender). 3. To determine whether impulsivity mediates the association between simulated serotonin function and HRB. We will test this mediation hypothesis using multiple-regression analysis. The revised application refines our analytic strategy and provides more detail regarding our proposed computational model that captures some of the dynamic interactions in the serotonin system across levels of analysis. Our ultimate goal is to contribute to a better understanding of the mechanisms underlying the propensity to engage in HRB, which would provide insights into the complex architecture underlying common mental illnesses and behavioral disorders (e.g. pathological gambling, addiction) and inform prevention and treatment efforts. A better understanding of the underlying mechanisms that mediate vulnerability to common mental illness and behavioral disorders is likely to aid in development of treatment and prevention efforts by helping to identify those at highest risk and leverage points to influence the system. The ultimate goal is a better understanding of the complex architecture that underlies risk for common mental illnesses and behavioral disorders such as pathological gambling, eating disorders and substance abuse across levels of analysis from genes to behaviors. [unreadable] [unreadable] [unreadable]